Maternal alcohol (ethanol) consumption results in marked adverse effects on neuroendocrine activity and regulation of both the maternal female and the fetus, and effects on the offspring typically persist into adulthood. Whether ethanol-induced endocrine imbalances contribute to the etiology of Fetal Alcohol Spectrum Disorder (FASD) is unknown, but it is certainly a possibility. Of particular relevance to the present proposal is the concept that ethanol-induced disturbances of the reciprocal interconnections between maternal and fetal endocrine systems, and in particular, the hypothalamic-pituitary-adrenal (HPA) axes, may provide a final common pathway by which fetal or early programming can occur, i.e., a route through which prenatal exposure to drugs, environmental stressors or other aversive stimuli produces long-lasting behavioral or physiological consequences. We have shown that prenatal ethanol exposure reprograms the fetal HPA axis such that HPA tone is increased throughout life. Increased exposure to endogenous glucocorticoids over the lifespan can alter behavioral and physiological responsiveness, and predispose the organism to the development of diseases later in life. Alterations in immune function may be one of the consequences of fetal programming. Indeed, data from our lab and others demonstrate marked deficits in adaptive immunity in fetal ethanol-exposed offspring. One possible mechanism mediating fetal programming may involve the effects of prenatal ethanol on regulation of gene expression. Effects that persist into adulthood, such as the changes observed in HPA regulation, could be due to epigenetic mechanisms (eg. Weaver et al., 2004). Such mechanisms include DNA methylation and/or changes in chromatin structure, and are vital in controlling how genes interact with the environment. Studies described in the present proposal will utilize the adjuvant-induced arthritis (AA) model to elucidate mechanisms underlying prenatal ethanol effects on neuro-immune function. AA is a T-cell dependent model of chronic inflammatory stress that is widely used as a model of human rheumatic disease. Of relevance to the present proposal, AA appears to represent a selective adaptation/maladaptation of the HPA axis, resulting in persistent increased HPA drive during the inflammatory phase of disease, and an altered corticosterone (CORT) response to stressors. In view of the well-established alterations in HPA activity and immune-HPA interactions in our animal model of prenatal ethanol exposure (see Background), the AA model is an ideal one for our studies. It allows us to investigate how ethanol exposure in utero may increase vulnerability to the pathological consequences of chronic unrelenting stress in a context in which it may be experienced in humans. Our preliminary data indicate that fetal ethanol-exposed (E) females exhibit compromised weight gain, a more severe and more prolonged course of AA, and increased basal ACTH levels compared to their pair-fed (PF) and ad libitum-ted control (C) counterparts. These data are highly novel in that the literature to date (including our own studies) suggests that prenatal ethanol-induced immune deficits occur primarily in T cell-dependent aspects of immunity, and primarily in males. Our preliminary data are the first to demonstrate marked neuro-immune effects in fetal ethanol-exposed females. The present proposal extends these data in several important new directions, focusing specifically on HPA and neuro-immune function, as well as HPA-immune interactions. In addition, as a first approach to elucidating possible mechanisms underlying the differential vulnerability to disease seen in ethanol-exposed vs control offspring, we will examine fluctuations in global gene expression with the aim of identifying signature gene expression profiles. This approach provides an unbiased assessment of ethanol and stress effects on gene expression, and will set the stage to determine which changes are persistent, and if those that persist are mediated by epigenetic mechanisms. The proposed studies will test two hypotheses: 1) Prenatal ethanol exposure results in altered neuro-immune function through the mechanism of fetal programming, involving either direct programming of the fetal immune system by ethanol, indirect effects via programming of fetal HPA activity, or (and probably most likely) a combination of direct and indirect effects; 2) A mechanism mediating fetal programming of neuro-immune function may involve the effects of ethanol on gene expression profiles.